Background: Continuous positive airway pressure (CPAP) is widely used in preterm infants. Identification of readiness for weaning from CPAP can balance benefits with risks of CPAP exposure. We tested the hypothesis that preterm infants that successfully transition off CPAP have higher oxygen saturations prior to weaning compared with infants who fail weaning from CPAP. Methods: This was a single-center-matched case–control study in infants ≤30 weeks’ gestation receiving ≤30% FiO2 weaned off CPAP during the first postnatal week. Cases were infants placed back on CPAP within 7 days of being taken off CPAP, whereas control infants remained off CPAP for 7 consecutive days following CPAP discontinuation. Infants were matched on gestational age at birth (±10 days). Prospectively collected histograms detailing the distribution of oxygen saturations prior to CPAP discontinuation were compared between cases and controls. Results: Over a 12-month monitoring period, 36 infants met inclusion criteria. Baseline characteristics, morbidities, and clinical variables did not differ between cases and controls. Controls achieved oxygen saturations of 95–97 and 97–100% for longer duration compared to cases (p ' 0.05). Conclusions: In preterm infants with RDS receiving CPAP and ≤30% FiO2, infants with higher oxygen saturations had greater success in transitioning off CPAP.